期刊
LEUKEMIA RESEARCH
卷 25, 期 10, 页码 891-900出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0145-2126(01)00047-9
关键词
cytarabine; apoptosis; deoxycytidine kinase; dCTP; CTP synthetase; cyclopentenyl cytosine; T-ALL
Cyclopentenyl cytosine (CPEC) is a nucleoside-analogue that decreases the concentrations of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP) in leukemic cells by inhibiting the enzyme CTP synthetase, resulting in a decreased synthesis of RNA and DNA. Low concentrations of dCTP facilitate the phosphorylation Of 1-beta -D arabinofuranosyl cytosine (araC) and the incorporation of arabinofuranosyl cytosine triphosphate (araCTP) into DNA. Apoptosis and necrosis were analyzed by flowcytometric detection of fluorescence-labeled Annexin V in a human T-lymphoblastic MOLT-3 cell-line after incubations with CPEC and/or araC. CPEC induced apoptosis and necrosis in a concentration- (50-300 nM) and time-dependent (8-16 h) way. The observed necrosis proved to be secondary to apoptosis as the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) completely blocked the CPEC-induced apoptosis and necrosis. Coincubation of various concentrations of CPEC and araC for 16h showed a significant additive effect on the occurrence of apoptosis and (secondary) necrosis. In contrast, a preincubation with 37.5 nM of CPEC for 24 h, which by itself caused only minor apoptosis (4%), followed by a coincubation for 16 h with 62.5 nM of araC (7% of apoptotic. cells), showed a synergistic effect on the induction of apoptosis (27%, P < 0.001). Growth-inhibition experiments with CPEC and araC under various conditions showed an additive effect on the araC-induced growth-inhibition after 48 h. The results indicate that the cytotoxicity of araC can be increased in T-lymphoblasts by CPEC. (C) 2001 Elsevier Science Ltd. All rights reserved.
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